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Study of the Safety of Intravenous Artesunate

Primary Purpose

Malaria, Malaria, Cerebral

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Intravenous Artesunate
Placebo
Sponsored by
U.S. Army Medical Research and Development Command
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria focused on measuring artesunate, artemisinin, falciparum

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Healthy adult males and non-pregnant, non-lactating females Have a normal ECG that may include benign PAC's and PVC's, 1st degree AV block, 2nd degree AV block, Wenckebach Have a normal blood pressure (BP) and heart rate (HR). These will be measured after resting supine for about 3 minutes. Normal BP is defined as less than 140 mm Hg systolic and less than 90 mm Hg diastolic. Normal baseline HR is 50 to 90 bpm without symptoms. Body mass index between 18 and 29 kg/m**2 or, if out of range, not clinically significant (within 15% of their ideal body weight). Be able to verbalize understanding of the consent form, provide written informed consent and verbalize willingness to complete study procedures Have a physical examination that demonstrates no clinically significant contraindication for participating in the study. This would include documentation of any abnormal movements suggesting neurological pathology and ECG tracings to document an abnormalities in cardiac conduction If female, have a negative serum pregnancy test at screening and urine pregnancy test on pre-admission and admission, or be postmenopausal, or have had a hysterectomy, or have been sterilized, AND, if still able to bear children, agree to practice effective contraception for the duration of the study and for a period of 12 weeks after stopping study drug. Active duty participants must be on leave during the inpatient phase of the study. Exclusion Criteria: Have received any investigational drug or vaccine in the period 0 to 16 weeks before entry to the study. Have been on a liquid protein diet in the last year Have any clinically important physical findings, laboratory abnormalities, or histories of Rx or OTC drug use that may, in the judgement of a study investigator, impact study interpretation or affect subject safety Have used any prescription drugs within 14 days prior to admission or most non-prescription drugs including herbals or dietary supplements within 7 days prior to admission (at the investigator's discretion). Existence of any surgical or medical condition that, in the judgement of the clinical investigator, might interfere with the distribution, metabolism or excretion of the drug Presence of history of drug allergy requiring treatment. Hay fever is allowed unless it is active or has required treatment within the previous 2 months Donation or loss of greater than 400 ml of blood in the period 0 to 12 weeks before entry to the study. Serious adverse reaction or hypersensitivity to any drug, particularly artemisinin derivatives CAGE (screening test for alcoholism) postitive (2 out of 4 criteria) or has a history of recent alcohol abuse Use of illicit drugs Family history (in 1st degree relatives) of sudden cardiac death or prolonged QT/QTc syndrome History of seizure (excluding febrile seizures in childhood), episodes of unexplained syncope, or trouble with balance, undiagnosed hearing deficits, and other neurological disorder History of severe psychiatric disorder or hospitalization for severe psychiatric disorder Current job or personal habit of reversed sleep-wake cycle History of cardiac disease to include cardiomyopathy, valvular disease, arrhythmia, ischemia, or enlarged heart Presence of hepatitis B surface antigen (Hbs-Ag), hepatitis C antibody (antiHCV) or HIV type 1 at screening A finding or history of hematuria (excluding menses-related hematuria) during subject screening

Sites / Locations

  • Uniformed Services University of the HEalth Sciences

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

2 mg/kg Intravenous Artesunate

4 mg/kg Intravenous Artesunate

8 mg/kg Intravenous Artesunate

Placebo

Arm Description

2 mg/kg of Intravenous artesunate

4 mg/kg of Intravenous artesunate

8 mg/kg of Intravenous artesunate

Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate.

Outcomes

Primary Outcome Measures

Number of Participants With AEs
The general strategy of the safety analysis was to examine the clinical tolerability and laboratory safety parameter data and determine if there were any trends amongst the dose levels concerning all AEs and drug related AEs.
Number of Participants With AEs Occurring in Greater Frequency in the 2.0 mg/kg IV AS Group Then in the Placebo Group to Access Safety and Tolerability of AS
Comparison of number of participants with AEs reported for the placebo control and those treated with the 2.0 mg/kg of IV AS to access safety and tolerability

Secondary Outcome Measures

Cardiovascular Responses: Number of Participants With Changes in Blood Pressure and Heart Rate After Infusion
Cardiovascular Responses: Number of participants with changes in blood pressure and heart rate after infusion to determine change from baseline
Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)
For artesunic acid, AUC0-last was determine for each dose; as well as the total area under the curve (AUClastTOTAL), calculated as the sum of AUClast for each of the doses (ng*hr/mL)
Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)
For the predicted concentration at the time of dose administration (C0) was determine for each dose (ng/mL)
Range of Pharmacokinetic Parameters for Dihydroartemisinin (DHA) After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)
For DHA, AUC24, and AUClast were calculated for each dose, as well as the total area under the curve extrapolated to infinite time (AUC∞TOTAL), calculated as the sum of AUC24 for each dose +C24/λz.
Cmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)
Cmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (ng/mL)
Tmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (hr)
Tmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (hr)

Full Information

First Posted
February 14, 2006
Last Updated
February 2, 2018
Sponsor
U.S. Army Medical Research and Development Command
Collaborators
Walter Reed Army Institute of Research (WRAIR)
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1. Study Identification

Unique Protocol Identification Number
NCT00292942
Brief Title
Study of the Safety of Intravenous Artesunate
Official Title
A Phase 1 Double-Blind, Placebo-Controlled, Randomized Multiple Dose Escalation Study to Evaluate the Safety, Tolerance, and Pharmacokinetics/Pharmacodynamics of a New GMP Formulation of Intravenous Artesunate if Healthy Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
June 12, 2006 (Actual)
Primary Completion Date
January 17, 2007 (Actual)
Study Completion Date
January 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
U.S. Army Medical Research and Development Command
Collaborators
Walter Reed Army Institute of Research (WRAIR)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to establish the safety, tolerability, and pharmacokinetics of a multiple dose of the antimalarial drug artesunate.
Detailed Description
This study was a Phase 1b, randomized, double-blind, placebo-controlled trial using multiple ascending doses of intravenous artensunate (AS) to determine it's safety, tolerability, and PK in healthy subjects. Subjects were screened within 21 days of dosing. At the screening visit, subject underwent baseline assessments: vital signs were recorded; a physical examination, urinalysis, urine drug screen, and urine pregnancy test were performed; a complete blood cell count (CBC) with differential and indices, reticulocyte count, coagulation markers, and blood chemistry assessments were performed and medical and medication history was collected. Eligible subjects were scheduled for a 6-hour pre-dose electrocardiogram (ECG) and vital sign assessment with measurements taken at approx. the same times as Day 1 (dosing day). On Day 0, subjects were admitted to the clinical pharmacology unit to begin the inpatient phase of the study. Subjects had a brief physical examination and all procedures for the inpatient stay were reviewed. On Day 1, pre-dose vital signs and ECG were performed. Subjects then received study drug or placebo by IV bolus infusion. Subjects were closely monitored by evaluating hemodynamic measurements, periodic ECGs, and assessment of spontaneously reported AEs. Blood was drawn for blood count and chemistry analysis 6h and 24h after each dose. PK blood samples were drawn pre-dose and approx. 5min, 20min, 40min, 1h, 2h, 4h, 6h, and 24h after each dose. On Days 2 and 3 subjects received their second and third doses, respectively, of study drug or placebo with the same monitoring and laboratory measurements as for the first dose. Subjects were discharged 24 hours after the 3rd dose of drug or placebo and were followed as outpatients on Days 7, 10, and 15.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Malaria, Cerebral
Keywords
artesunate, artemisinin, falciparum

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
2 mg/kg Intravenous Artesunate
Arm Type
Experimental
Arm Description
2 mg/kg of Intravenous artesunate
Arm Title
4 mg/kg Intravenous Artesunate
Arm Type
Experimental
Arm Description
4 mg/kg of Intravenous artesunate
Arm Title
8 mg/kg Intravenous Artesunate
Arm Type
Experimental
Arm Description
8 mg/kg of Intravenous artesunate
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate.
Intervention Type
Drug
Intervention Name(s)
Intravenous Artesunate
Other Intervention Name(s)
IV AS
Intervention Description
Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Mannitol
Intervention Description
Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.
Primary Outcome Measure Information:
Title
Number of Participants With AEs
Description
The general strategy of the safety analysis was to examine the clinical tolerability and laboratory safety parameter data and determine if there were any trends amongst the dose levels concerning all AEs and drug related AEs.
Time Frame
up to 21 days
Title
Number of Participants With AEs Occurring in Greater Frequency in the 2.0 mg/kg IV AS Group Then in the Placebo Group to Access Safety and Tolerability of AS
Description
Comparison of number of participants with AEs reported for the placebo control and those treated with the 2.0 mg/kg of IV AS to access safety and tolerability
Time Frame
up to 21 days
Secondary Outcome Measure Information:
Title
Cardiovascular Responses: Number of Participants With Changes in Blood Pressure and Heart Rate After Infusion
Description
Cardiovascular Responses: Number of participants with changes in blood pressure and heart rate after infusion to determine change from baseline
Time Frame
screening, on Day -1, on Days 1, 2, and 3, and at each follow-up visit
Title
Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)
Description
For artesunic acid, AUC0-last was determine for each dose; as well as the total area under the curve (AUClastTOTAL), calculated as the sum of AUClast for each of the doses (ng*hr/mL)
Time Frame
Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion
Title
Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)
Description
For the predicted concentration at the time of dose administration (C0) was determine for each dose (ng/mL)
Time Frame
Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion
Title
Range of Pharmacokinetic Parameters for Dihydroartemisinin (DHA) After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)
Description
For DHA, AUC24, and AUClast were calculated for each dose, as well as the total area under the curve extrapolated to infinite time (AUC∞TOTAL), calculated as the sum of AUC24 for each dose +C24/λz.
Time Frame
Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion
Title
Cmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)
Description
Cmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (ng/mL)
Time Frame
Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion
Title
Tmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (hr)
Description
Tmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (hr)
Time Frame
Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy adult males and non-pregnant, non-lactating females Have a normal ECG that may include benign PAC's and PVC's, 1st degree AV block, 2nd degree AV block, Wenckebach Have a normal blood pressure (BP) and heart rate (HR). These will be measured after resting supine for about 3 minutes. Normal BP is defined as less than 140 mm Hg systolic and less than 90 mm Hg diastolic. Normal baseline HR is 50 to 90 bpm without symptoms. Body mass index between 18 and 29 kg/m**2 or, if out of range, not clinically significant (within 15% of their ideal body weight). Be able to verbalize understanding of the consent form, provide written informed consent and verbalize willingness to complete study procedures Have a physical examination that demonstrates no clinically significant contraindication for participating in the study. This would include documentation of any abnormal movements suggesting neurological pathology and ECG tracings to document an abnormalities in cardiac conduction If female, have a negative serum pregnancy test at screening and urine pregnancy test on pre-admission and admission, or be postmenopausal, or have had a hysterectomy, or have been sterilized, AND, if still able to bear children, agree to practice effective contraception for the duration of the study and for a period of 12 weeks after stopping study drug. Active duty participants must be on leave during the inpatient phase of the study. Exclusion Criteria: Have received any investigational drug or vaccine in the period 0 to 16 weeks before entry to the study. Have been on a liquid protein diet in the last year Have any clinically important physical findings, laboratory abnormalities, or histories of Rx or OTC drug use that may, in the judgement of a study investigator, impact study interpretation or affect subject safety Have used any prescription drugs within 14 days prior to admission or most non-prescription drugs including herbals or dietary supplements within 7 days prior to admission (at the investigator's discretion). Existence of any surgical or medical condition that, in the judgement of the clinical investigator, might interfere with the distribution, metabolism or excretion of the drug Presence of history of drug allergy requiring treatment. Hay fever is allowed unless it is active or has required treatment within the previous 2 months Donation or loss of greater than 400 ml of blood in the period 0 to 12 weeks before entry to the study. Serious adverse reaction or hypersensitivity to any drug, particularly artemisinin derivatives CAGE (screening test for alcoholism) postitive (2 out of 4 criteria) or has a history of recent alcohol abuse Use of illicit drugs Family history (in 1st degree relatives) of sudden cardiac death or prolonged QT/QTc syndrome History of seizure (excluding febrile seizures in childhood), episodes of unexplained syncope, or trouble with balance, undiagnosed hearing deficits, and other neurological disorder History of severe psychiatric disorder or hospitalization for severe psychiatric disorder Current job or personal habit of reversed sleep-wake cycle History of cardiac disease to include cardiomyopathy, valvular disease, arrhythmia, ischemia, or enlarged heart Presence of hepatitis B surface antigen (Hbs-Ag), hepatitis C antibody (antiHCV) or HIV type 1 at screening A finding or history of hematuria (excluding menses-related hematuria) during subject screening
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter J Weina, MD, PhD
Organizational Affiliation
Walter Reed Army Institute of Research (WRAIR)
Official's Role
Study Director
Facility Information:
Facility Name
Uniformed Services University of the HEalth Sciences
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20814-4799
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
WRAIR

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Study of the Safety of Intravenous Artesunate

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